This proosal is a study of natural and induced resistance of mice to the proliferation of hemopoietic tumors. The investigations are focused on the immunobiology and heterogeneity of effector systems; on regulatory mechanisms; and on genetic controls or responsiveness, target determinants, and differentiation of effector and regulatory cell lines. Mutant genes affecting differentiation and maturation of given cell lines (e.g., beige), or interactions between cells of different lineages (e.g., osteopetrosis) serve to identify relevant functions. The expression of Hemopoietic-histocompatibility (Hh) gene products on normal hemopoietic stem cells and leukemia-lymphoma cells is central to the project since recognition of these structures by cells of the lymphoid system leads to inhibition and/or rejection of target cells in vivo (i.e., hybrid and allogeneic resistance) and to cytotoxicity in vitro (i.e., primary F1 anti-parent cell-mediated lympholysis). Emphasis will be placed not only on Hh-controlled but also on other cellular structures that serve as targets for mouse reactivities against autologous or syngeneic tumors. Such "autoreactivities" are mediated by effectors belonging to the natural killer (NK) and cytotoxic T lymphocyte (CTL) classes. Resistance to parental lymphoma grafts by irradiated F1 hybrid mice involves NK-like mechanisms since effectors need not be induced and are relatively radioresistant, thymus independent, modulated by interferon, yet capable of recognizing specific gene products and causing graft rejection within 18-96 hours. The in vitro activation of F1 anti-parent CTL involves different mechanisms since responder cells must be stimulated and are radiosensitive as well as thymus dependent. F1 anti-parent CTL recognize the products of genes that are indistinguishable from Hh genes by recombinant analysis. Experiments are performed in vivo (bioassays for resistance for graft proliferation) and in vitro (induction of specific CTL and assessment of natural cytotoxicity) so as to characterize effector and suppressor cell systems. The distinct anti-Hh reactivities so detected may well regulate hemopoiesis under physiologic conditions and suppress leukemogenesis.